The Requirement of Linker for Activation of T Cells in the Primary and Memory Responses of CD8 T Cells

Ou-Yang, Chih-wen; Zhu, Minghua; Sullivan, Sarah; Fuller, Deirdre M.; Zhang, Weiguo

doi:10.4049/jimmunol.1203163

Cited by 6 publications

(6 citation statements)

References 36 publications

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“…A number of studies have correlated the kinetics of CD8 responses with external factors like the duration of antigen availability and the presence of costimulation (6,8). More recently, a role for T cell receptor (TCR)-mediated signaling (9,10) and cytokine-mediated signaling (11,12) in shaping primary and memory CD8 responses has also come to the fore. However, the signaling mechanisms that integrate these diverse extracellular cues to modulate the magnitude and quality of CD8 immune responses remain to be fully understood.…”

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confidence: 99%

Role of Tumor Suppressor TSC1 in Regulating Antigen-Specific Primary and Memory CD8 T Cell Responses to Bacterial Infection

et al. 2014

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The serine/threonine kinase mammalian/mechanistic target of rapamycin (mTOR) integrates various environmental cues such as the presence of antigen, inflammation, and nutrients to regulate T cell growth, metabolism, and function. The tuberous sclerosis 1 (TSC1)/TSC2 complex negatively regulates the activity of an mTOR-containing multiprotein complex called mTOR complex 1. Recent studies have revealed an essential cell-intrinsic role for TSC1 in T cell survival, quiescence, and mitochondrial homeostasis. Given the emerging role of mTOR activity in the regulation of the quantity and quality of CD8 T cell responses, in this study, we examine the role of its suppressor, TSC1, in the regulation of antigen-specific primary and memory CD8 T cell responses to bacterial infection. Using an established model system of transgenic CD8 cell adoptive transfer and challenge with Listeria monocytogenes expressing a cognate antigen, we found that TSC1 deficiency impairs antigen-specific CD8 T cell responses, resulting in weak expansion, exaggerated contraction, and poor memory generation. Poor expansion of TSC1-deficient cells was associated with defects in survival and proliferation in vivo, while enhanced contraction was correlated with an increased ratio of short-lived effectors to memory precursors in the effector cell population. This perturbation of effector-memory differentiation was concomitant with decreased expression of eomesodermin among activated TSC1 knockout cells. Upon competitive adoptive transfer with wild-type counterparts and antigen rechallenge, TSC1-deficient memory cells showed moderate defects in expansion but not cytokine production. Taken together, these findings provide direct evidence of a CD8 T cell-intrinsic role for TSC1 in the regulation of antigen-specific primary and memory responses. C D8 T cells play a critical role in clearing several types of microbial infections by mounting robust cytotoxic T lymphocyte (CTL) responses that kill infected cells. A typical CTL response is characterized by the presence of an effector phase, a contraction phase, and a memory maintenance phase (1, 2). During the expansion phase, naive CD8 cells are activated by antigenpresenting cells (APCs) in secondary lymphoid organs and undergo rapid clonal expansion. At the peak of the response, the population of CD8 effectors is heterogeneous and consists of a majority of short-lived effector cells (SLECs) and a small pool of memory-precursor effector cells (MPECs) (3, 4). Following antigen clearance, 90 to 95% of the CD8 effectors undergo apoptosis during the contraction phase (5, 6). At this stage, MPECs are thought to preferentially contribute to the formation of a small but stable population of long-lived memory cells. These memory cells are capable of self-renewal in response to cytokines such as interleukin-15 (IL-15) and respond more rapidly than naive cells to antigen reexposure (7). A number of studies have correlated the kinetics of CD8 responses with external factors like the duration of antigen availability and ...

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confidence: 99%

Role of Tumor Suppressor TSC1 in Regulating Antigen-Specific Primary and Memory CD8 T Cell Responses to Bacterial Infection

et al. 2014

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“…Linker for activation of T cells (LAT), a transmembrane adaptor protein that serves as a signaling hub and plays a key role in the early stages of TCR activation signaling, is one of the important substrates for ZAP‐70 . Intracellular tyrosine residues of LAT are phosphorylated by ZAP‐70 and activate downstream adaptor molecules phosphoinositide‐specific phospholipase C γ 1 (PLC γ 1), growth factor receptor‐bound protein 2 (Grb2) and Grb2‐related adaptor downstream of Shc (Gads), which then result in the activation of cytosolic Ca 2+ and multiple pathways such as the PLCγ1, phosphoinositide 3‐kinase (PI3K) and mitogen‐activate protein kinase (MAPK) pathways. These pathways control T‐cell maturation, proliferation, activation and differentiation .…”

Section: Introductionmentioning

confidence: 99%

Protein 4.1R negatively regulates CD8⁺ T‐cell activation by modulating phosphorylation of linker for activation of T cells

Fan

et al. 2019

Immunology

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Protein 4.1R, an 80 000 MW membrane skeleton protein, is a vital component of the red blood cell membrane cytoskeleton that stabilizes the spectrin-actin network and regulates membrane properties of deformability and mechanical stability. It has been shown that 4.1R is expressed in T cells, including CD8 + T cells, but its role in CD8 + T cells remains unclear. Here, we have explored the role of 4.1R in CD8 + T cells using 4.1R À/À mice. Our results showed that cell activation, proliferation and secretion levels of interleukin-2 and interferon-c were significantly increased in 4.1R À/À CD8 + T cells. Furthermore, the phosphorylation levels of linker for activation of T cells (LAT) and its downstream signaling molecule extracellular signal-regulated kinase were enhanced in the absence of 4.1R. In vitro co-immunoprecipitation experiments showed a direct interaction between 4.1R and LAT. Moreover, 4.1R À/À CD8 + T cells and mice exhibited an enhanced T-cell-dependent immune response. These data enabled the identification of a negative regulation function for 4.1R in CD8 + T cells by a direct association between 4.1R and LAT, possibly through inhibiting phosphorylation of LAT and then modulating intracellular signal transduction.

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“…Here, we used this newly established genetic tool to evaluate the role of TCR signaling in DETCs by deleting Linker Activation in T cell (LAT), an essential signaling molecule downstream of TCR(20). LAT has been shown to play an essential role in the development of all T cells, including DETCs(21), and proper function, survival, and homeostatic maintenance of αβ T cells(22–24). Our study showed that LAT deletion impaired the activation of DETCs in response to TCR stimulation.…”

Section: Introductionmentioning

confidence: 99%

Differential Requirements of TCR Signaling in Homeostatic Maintenance and Function of Dendritic Epidermal T Cells

Zhang

Jiao

et al. 2015

The Journal of Immunology

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Dendritic Epidermal T Cells (DETCs) are generated exclusively in the fetal thymus and maintained in the skin epithelium throughout postnatal life of the mouse. DETCs have restricted antigenic specificity due to their exclusive usage of a canonical TCR. Although the importance of the TCR in DETC development has been well established, the exact role of TCR signaling in DETC homeostasis and function remains incompletely defined. Here, we investigated TCR signaling in fully matured DETCs by lineage-restricted deletion of the Lat gene, an essential signaling molecule downstream of the TCR. We found that Lat deletion impaired TCR-dependent cytokine gene activation and the ability of DETC undergoing proliferative expansion. However, LAT-deficient DETCs were able to maintain long-term population homeostasis even though with reduced proliferation rate. Mice with Lat deletion in DETCs exhibited delayed wound healing accompanied by impaired clonal expansion within the wound area. Our study revealed differential requirements of TCR signaling in homeostatic maintenance of DETCs and in their effector function during wound healing.

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The Requirement of Linker for Activation of T Cells in the Primary and Memory Responses of CD8 T Cells

Cited by 6 publications

References 36 publications

Role of Tumor Suppressor TSC1 in Regulating Antigen-Specific Primary and Memory CD8 T Cell Responses to Bacterial Infection

Role of Tumor Suppressor TSC1 in Regulating Antigen-Specific Primary and Memory CD8 T Cell Responses to Bacterial Infection

Protein 4.1R negatively regulates CD8⁺ T‐cell activation by modulating phosphorylation of linker for activation of T cells

Differential Requirements of TCR Signaling in Homeostatic Maintenance and Function of Dendritic Epidermal T Cells

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The Requirement of Linker for Activation of T Cells in the Primary and Memory Responses of CD8 T Cells

Cited by 6 publications

References 36 publications

Role of Tumor Suppressor TSC1 in Regulating Antigen-Specific Primary and Memory CD8 T Cell Responses to Bacterial Infection

Role of Tumor Suppressor TSC1 in Regulating Antigen-Specific Primary and Memory CD8 T Cell Responses to Bacterial Infection

Protein 4.1R negatively regulates CD8+ T‐cell activation by modulating phosphorylation of linker for activation of T cells

Differential Requirements of TCR Signaling in Homeostatic Maintenance and Function of Dendritic Epidermal T Cells

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Protein 4.1R negatively regulates CD8⁺ T‐cell activation by modulating phosphorylation of linker for activation of T cells